Abstract Building on our successful primate model studies, we aim to develop a one-time treatment for durable remission of human immunodeficiency virus (HIV) in the absence of antiretroviral medications. This treatment is an autologous HIV-specific chimeric antigen receptor (CAR, specifically CD4-MBL-CAR) T cell therapy that targets B cell follicles1,2. B cell follicles are an immune protected site that permit viral replication due to low levels of virus-specific CD8 T cells3?6. Our preclinical CAR T cell pilot studies in a simian immunodeficiency virus (SIV)- infected rhesus macaque model of HIV indicated that this immunotherapy is safe and effective. Here, we propose to develop and evaluate a comparable human T cell immunotherapy. Virus-specific CD8 T cells exert potent antiviral activity against HIV-1 and SIV both in vitro and in vivo. Nevertheless, despite abundant CD8 T cell responses in HIV-1-infected humans and SIV-infected macaques, these cells are unable to fully suppress virus replication. This inadequate suppression is likely due to the fact that the majority of HIV-1 and SIV replication occurs in CD4+ T cells7?11 concentrated within B cell follicles in secondary lymphoid tissues, where relatively few virus-specific CD8 T cells reside3?6. In fact, we showed that the effector to target ratio of in vivo effector virus-specific CD8 T cell to target SIV RNA+ cells is >40-fold lower inside compared to outside of B cell follicles in lymphoid tissues during SIV infection in rhesus macaque5. Furthermore, we revealed that the majority of virus-specific CD8 T cells fail to express the follicular homing molecule CXCR55, likely explaining low levels of virus-specific CD8 T cells localizing to and surveilling B cell follicles. These data suggest that the inability of HIV- and SIV-specific CD8 T cells to fully suppress virus replication may be due to a deficiency of virus-specific CD8 T cells in B cell follicles. Based on these findings and the success of our preclinical primate studies, we propose to develop an HIV-specific CD4-MBL-CAR T cell therapy that employs the follicular homing molecule CXCR5 to direct the migration of HIV-specific T cells to B cell follicles. We specifically propose the following aims, 1) Develop human CD4-MBL-CAR/CXCR5 T cells, 2) Determine the phenotype of human CD4-MBL-CAR/CXCR5 T cells, 3) Determine the function of human CD4-MBL-CAR/CXCR5 T cells. Our proposed studies to develop human CD4-MBL-CAR/CXCR5 T cells that localize to and function in lymphoid B cell follicles may lead to durable remission of HIV infection in the absence of antiretroviral drugs.